Keros Therapeutics, Inc. · NASDAQ:KROS
Keros Therapeutics — Technical Presentation (November 2021)
14 slides from Keros Therapeutics's technical presentation, Nov 14, 2021
Slide 1: KER-012 Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model
KER-012, a Novel Modified ActRII Ligand Trap, Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model of Right Ventricle Overload Keith Babbs, Chris Materna, ffolliott Fisher, Jasbir Seehra, Jennifer Lachey Keros Therapeutics, Inc. Lexington, MA, USA 14 November 2021| CONFIDENTIAL
Slide 2: Disclosures
Disclosures Keith Babbs, Chris Materna, ffolliott Fisher, Jasbir Seehra, and Jennifer Lachey are employees and stockholders of Keros Therapeutics, Inc.
Slide 3: Overview: Pulmonary Arterial Hypertension (PAH)
Overview: Pulmonary Arterial Hypertension (PAH) • Debilitating disorder with an estimated prevalence of 10,000 to 20,000 cases in the U.S. (Prins 2016, Wijeratne 2018) • Driven by pulmonary endothelial dysfunction and vascular remodeling leading to increased wall thickening and resistance to blood f
Slide 4: Overview: PAH and TGF-b signaling
Overview: PAH and TGF-b signaling • In healthy vasculature, homeostasis is achieved by balanced signaling through SMAD1/5/9 and SMAD2/3, the canonical signaling proteins for the TGF-b superfamily. • PAH has been associated with dysregulated TGF-b signaling, favoring signaling through SMAD2/3 (Machad
Slide 5: Rebalancing Signaling
Rebalancing Signaling • Increasing SMAD1/5/9 signaling or decreasing SMAD2/3 signaling may restore homeostasis. • Promoting SMAD1/5/9 by administration of BMP9 reversed RV and pulmonary dysfunction in models of PAH (Long 2015). • Inhibition of TGF-b2 and 3 by administration of TGFbRII-Fc reduced PAH
Slide 6: ActRII Ligand Traps Affect Bone, Vasculature, and Erythropoiesis
ActRII Ligand Traps Affect Bone, Vasculature, and Erythropoiesis • Signaling through SMAD1/5/9 and SMAD2/3 are known to regulate multiple systems, including bone, vasculature and erythropoiesis (Zhang 2017, Itoh 2012, Blank 2011, Song 2009). • Acceleron has disclosed that Sotatercept (ActRIIA-Fc) ha
Slide 7: Research Questions
Research Questions • Are the effects on bone, RBC and vasculature dependent on one another (i.e., can you have a therapeutic with more selective biology)? KER-012 is an investigational, modified ActRIIB ligand trap designed to inhibit SMAD2/3. Keros has previously demonstrated in preclinical studies
Slide 8: Pulmonary Arterial Banding (PAB)
Pulmonary Arterial Banding (PAB) RKER-012, a research form of KER-012, was evaluated in the PAB model to evaluate its effect on dysfunction resulting from RV overload • PAB increases RV pressure by mechanically restricting blood flow through the pulmonary artery. • 8 w.o. male C57Bl/6 mice (n=14-16/
Slide 9: PAB Increased PAP was confirmed in all PAB groups
PAB Increased PAP was confirmed in all PAB groups, verifying pressure overload Initial Final Values depicted are mean + SEM. ****p<0.0001 vs. Sham Initial; ##p<0.01, ####p<0.0001 vs. Sham Final
Slide 10: RKER-012 treatment resulted in improved cardiac dysfunction
RKER-012 treatment resulted in improved cardiac dysfunction End Systolic Pressure- Myocardial Volume Relationship Performance Index PAB induced cardiac dysfunction: • Increased ESPVR • Increased MPI RKER-012 decreased ESPVR and MPI. Values depicted are mean + SEM. ***p<0.001; ****p<0.0001 vs. Sham;
Slide 11: RKER-012 decreased cardiac remodeling
RKER-012 decreased cardiac remodeling Fulton Index RV Free Wall Thickness SHAM PAB+VEH PAB+ RKER-012 PAB induced cardiac remodeling: • Increased Fulton Index • Increased RV free wall thickness RKER-012 decreased Fulton Index and RV free wall thickness. Values depicted are mean + SEM. ****p<0.0001 vs
Slide 12: RKER-012 decreased cardiac fibrosis
RKER-012 decreased cardiac fibrosis Cardiac Fibrosis SHAM PAB+VEH PAB + RKER-012 Fibrotic Tissue • PAB induced formation of fibrotic tissue. • RKER-012 decreased cardiac fibrotic tissue. Values depicted are mean + SEM. ****p<0.0001 vs. Sham; ##p<0.01 vs. PAB + Vehicle
Slide 13: KER-012 Did Not Affect Hemoglobin or Red Blood Cells in Non-human Primates
KER-012 Did Not Affect Hemoglobin (HGB) or Red Blood Cells (RBC) in Non-human Primates • As discussed earlier, ActRII ligand traps have also been demonstrated to have pro- erythropoietic effects in humans, an effect which could be dose limiting in non- erythropoiesis-related diseases • Ligand traps
Slide 14: Summary/Conclusions
Summary/Conclusions • KER-012 is an investigational modified ActRIIB ligand trap designed to inhibit ligands that signal through SMAD2/3 to promote restoration of vascular homeostasis. • In a PAB model of RV pressure overload, RKER-012 showed direct cardiac benefit by decreasing: • Cardiac dysfuncti
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